It is generally supposed that foreign cells display immunogenic determinants on the cell membrane. Consequently the apparent inability of the human host to mount effective immune responses to such cells for example in pregnancy or cancer, poses an intriguing paradox. The proposed studies are based on recent observations, which indicate that both human trophoblasts and transformed or malignant cell lines, but not normal resting lymphocytes or fibroblasts, can bind normal host proteins, including albumin or plasminogen, and in particular, the ironbinding B-globulin, transferrin, to their cell membrances. The first objective of these studies is to investigate in detail the binding of transferrin and other host proteins to these cells, particularly in terms of the specificity of the reactions and mobility of the receptor sites. This will be accomplished by immunofluorescence and radioisotopic methods performed in parallel. Secondly, cells derived from solid tumors and patients with leukemia, and lymphocytes stimulated with mitogens, will be investigated to further determine the tissue distribution of transferrin receptors. Thirdly, attempts will be made to elucidate biological relevance of transferrin receptors, such as the effect of cellular uptake of transferrin upon subsequent binding of specific cell membrane antibodies, or on the cytotoxic potential of the latter in the presence of a complement source. Finally, membranes from selected cells bearing transferrin receptors will be solubilized, using various detergent protocols and fractionation to yield transferrin receptors. Although such purification will provide certain physicochemical data concerning transferrin receptors, the major purpose is the production of antibodies which can be used both in studies of their potential to block binding of transferrin and specific cell membrance antibodies, and also in further investigation of tissue distribution and other properties of transferrin receptors. These studies will provide information concerning the ability of certain normal host proteins to bind to cell membranes of various cells, and in addition to elucidating certain basic properties of such binding reactions will also allow preliminary conclusions to be drawn concerning nutrient, immunoregulatory and other possible biological roles of such receptors.